Composition for enhancing immunity comprising immune modulator and cationic liposome, and use of same

Abstract

The present invention relates to an immunity enhancing composition including an immune response modulator having a novel structure and, more specifically, to an immunity enhancing composition and a use of the same, wherein the immunity enhancing composition includes a lipopolysaccharide (LPS) analogue with reduced toxicity, and a cationic liposome. The present invention overcomes the physicochemical instability of a liposome, is advantageous in terms of production, transportation, and storage, and improves stability, thus being beneficial as an immune delivery system. In addition, the present invention includes an immune response modulator, and a cationic liposome, and thus exhibits an enhanced immunity-improving effect compared to the case in which an immune response modulator is used alone.

The invention claimed is: 
     
       1. A composition for enhancing immunity comprising:
 (a) an immune modulator represented by the following Formula 1: 
 
       
         
           
           
               
               
           
         
       
       wherein Glc is glucose, GlcN is glucosamine, HEP is heptose, KDO is 2-keto-3-deoxy-octonate, GlcNAc is N-acetylglucosamine, P is phosphate, and C to E are positions to which phosphate can be bonded, wherein each phosphate is bonded at a position selected from the group consisting of C, E, CD, CE, DE, and CDE of Formula 1; and
 (b) a cationic liposome. 
 
     
     
       2. The composition according to  claim 1 , wherein the cationic liposome is a cationic lipid selected from the group consisting of dimethyldioctadecylammonium bromide (DDA), 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 3β-[N-(N′,N′-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol), 1,2-dioleoyloxy-3-dimethylammonium propane (DODAP), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), 1,2-dimyristoleoyl-sn-glycero-3-ethylphosphocholine (14:1 Ethyl PC), 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine (16:0-18:1 Ethyl PC), 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (18:1 Ethyl PC), 1,2-distearoyl-sn-glycero-3-ethylphosphocholin (18:0 Ethyl PC), 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine (16:0 Ethyl PC), 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (14:0 Ethyl PC), 1,2-dilauroyl-sn-glycero-3-ethylphosphocholin (12:0 Ethyl PC), N1-[2-((1S)-1-[(3-aminopropyl)amino]-4- [di(3-amino-propyl)amino]butylcarboxamido)ethyl]3,4-di[oleyloxy]-benzamide (MVL5), 1,2-dimyristoyl-3-dimethylammonium-propane (14:0 DAP), 1,2-dipalmitoyl-3-dimethylammonium-propane (16:0 DAP), 1,2-distearoyl-3-dimethylammonium-propane (18:0 DAP), N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium (DOBAQ), 1,2-stearoyl-3-trimethylammonium-propane (18:0 TAP), 1,2-dipalmitoyl-3-trimethylammonium-propane (16:0 TA), 1,2-dimyristoyl-3-trimethylammonium-propane (14:0 TAP) and N4-cholesteryl-spermine (GL67). 
     
     
       3. The composition according to  claim 2 , wherein the cationic liposome further comprises a neutral lipid selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), phosphoethanol amine (PE), and phosphatidyl choline (PC). 
     
     
       4. A vaccine composition comprising:
 (a) an antigen; and 
 (b) the composition for enhancing immunity according to  claim 1  as an active ingredient. 
 
     
     
       5. The vaccine composition according to  claim 4 , wherein the antigen is selected from the group consisting of a peptide, a protein, a nucleic acid, a sugar, a pathogen, an attenuated pathogen, an inactivated pathogen, a virus, a virus-like particle (VLP), a cell or a cell fragment. 
     
     
       6. The vaccine composition according to  claim 4 , wherein the antigen is selected from the group consisting of an antigen of Zika virus, an antigen of Japanese encephalitis virus, an antigen of  Mycobacterium tuberculosis , an antigen of pertussis, an antigen of varicella-zoster virus, an antigen of  Haemophilus influenzae  type B (HIB), an antigen of Middle East Respiratory Syndrome (MERS) virus, an antigen of  Pseudomonas aeruginosa , an antigen of anthrax, an antigen of hepatitis A virus (HAV), an antigen of hepatitis B virus (HBV), an antigen of hepatitis C virus (HCV), an antigen of human immunodeficiency virus (HIV), an antigen of herpes simplex virus (HSV), an antigen of  Neisseria meningitidis , an antigen of  Corynebacterium diphtheria , an antigen of  Bordetella pertussis , an antigen of  Clostridium tetani , an antigen of human papilloma virus (HPV), an antigen of Enterococci, an antigen of  Staphylococcus aureus , an antigen of  Klebsiella pneumoniae , an antigen of  Acinetobacter baumannii , an antigen of  Enterobacter , an antigen of  Helicobacter pylori , an antigen of malaria, an antigen of a dengue virus, an antigen of  Orientia tsutsugamushi , an antigen of severe fever with thrombocytopenia syndrome Bunyavirus (SFTS Bunyavirus), an antigen of severe acute respitaroty syndrome-coronavirus (SARS-CoV), an antigen of an influenza virus, an antigen of an Ebola virus and an antigen of  Diplococcus pneumoniae.    
     
     
       7. The vaccine composition according to  claim 4 , wherein the vaccine is an inactivated vaccine, an attenuated vaccine, a subunit vaccine, a conjugate vaccine, a recombinant vaccine, a monovalent vaccine, a multivalent vaccine, or a mixed vaccine. 
     
     
       8. The vaccine composition according to  claim 4 , wherein the vaccine is selected from the group consisting of a Zika vaccine, a Japanese encephalitis vaccine, a tuberculosis vaccine, a pertussis vaccine, a varicella-zoster virus (VZV) vaccine, a varicella vaccine, a  Haemophilus influenzae  type B vaccine, a MERS vaccine, a  Pseudomonas aeruginosa  vaccine, a cancer vaccine, an anthrax vaccine, a HAV vaccine, an HBV vaccine, an HCV vaccine, an HIV vaccine, a meningococcal vaccine, a diphtheria vaccine, a tetanus vaccine, a multidrug-resistant bacteria vaccine, an Enterococci vaccine, a  Staphylococcus aureus  vaccine, a  Klebsiella pneumoniae  vaccine, an  Acinetobacter baumannii  vaccine, an  Enterobacter  vaccine, a  Helicobacter pylori  vaccine, a malaria vaccine, a dengue virus vaccine, an  Orientia tsutsugamushi  vaccine, a severe fever with thrombocytopenia syndrome Bunyavirus (SFTS bunyavirus) vaccine, a severe acute respiratory syndrome-coronavirus (SARS-CoV) vaccine, an Ebola virus vaccine, an influenza virus vaccine and a  Diplococcus pneumoniae  vaccine. 
     
     
       9. The vaccine composition according to  claim 4 , wherein the vaccine is a lyophilized formulation. 
     
     
       10. The vaccine composition according to  claim 8 , wherein the varicella-zoster virus (VZV) vaccine is in a ready-to-use form. 
     
     
       11. The vaccine composition according to  claim 4 , wherein the vaccine further comprises cholesterol, squalene or tricaprin. 
     
     
       12. The vaccine composition according to  claim 4 , wherein the vaccine further comprises saponin, Quil A or QS21 as a saponin-derived substance. 
     
     
       13. A method for preparing the composition for enhancing immunity according to  claim 1  comprising:
 (a) preparing a solution containing an immune modulator represented by the following Formula 1: 
 
       
         
           
           
               
               
           
         
         wherein Glc is glucose, GlcN is glucosamine, HEP is heptose, KDO is 2-keto-3-deoxy-octonate, GlcNAc is N-acetylglucosamine, P is phosphate, and C to E are positions to which phosphate can be bonded, wherein each phosphate is bonded at a position selected from the group consisting of C, E, CD, CE, DE, and CDE of Formula 1; 
         (b) dissolving a lipid in an organic solvent to prepare a lipid mixed solution; 
         (c) lyophilizing the lipid mixed solution of step (b) to remove the organic solvent; and 
         (d) rehydrating the substance obtained in step (c), and then mixing the substance with the solution of step (a), thereby forming a composition for enhancing immunity. 
       
     
     
       14. A method for preparing the vaccine composition according to  claim 4  comprising:
 (a) preparing a solution containing an immune modulator represented by the following Formula 1: 
 
       
         
           
           
               
               
           
         
         wherein Glc is glucose, GlcN is glucosamine, HEP is heptose, KDO is 2-keto-3-deoxy-octonate, GlcNAc is N-acetylglucosamine, P is phosphate, and C to E are positions to which phosphate can be bonded, wherein each phosphate is bonded at a position selected from the group consisting of C, E, CD, CE, DE, and CDE of Formula 1; 
         (b) dissolving a lipid in an organic solvent to prepare a lipid mixed solution; 
         (c) lyophilizing the lipid mixed solution of step (b) to remove the organic solvent; 
         (d) rehydrating the substance obtained in step (c), thereby forming a liposome; and 
         (e) adding the solution of step (a) and an antigen to the liposome of step (d), followed by lyophilizing again.